J. Org. Chem. 1991,56, 7336-7340
7336
TrifluoroisopropenylzincReagent as a Useful a-(Trifluoromethy1)ethenyl Carbanion Synthetic Equivalent. Preparation and Palladium-Catalyzed Coupling with Aryl Halides' B i a o Jiang* and Y u a n y a o
Table I. Preparation of TFPZ (2) from BTFP (l), Zn(Ag), and TMEDA reaction yield TMEDA cond" temp conversion of 2b entry (equiv) solvent (OC)/time (h) of l b (5%) (5%) 1 40124 0 0 Et20 2 0.5 40124 Et20 50 50 40124 3 1.0 100 98 EhO 4 THF 40124 0 0 5 0.5 THF 6019 50 47
Xu*
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Academia Sinica, 345 Lingling Lu, Shanghai 200032, China
6
Received January 30, 1991 (Revised Manuscript Received September 5, 1991)
In recent years, trifluoromethylated organic molecules have been drawing much attention due to their unique biological properties2and considerable effort has been paid to the exploitation of new synthetic routes to these fluorinated compound^.^ Trifluoromethylation,4fluorination,5 and the halogen exchange reaction6 are possible methods for introducing the trifluoromethyl group into a molecule. However, such methods are sometimes accompanied by low reactivity and low selectivity. Another approach is to prepare CF3-containingintermediates and utilize them as building blocks.' The latter route is now becoming an important strategy for the construction of trifluoromethylated molecules because it usually allows access to these CF3-substituted compounds under milder conditions and with a tolerance of functionalities. Therefore, the development of a simple method for the preparation of trifluoromethylated building blocks and their further utilization for the synthesis of desired CF3-containing compounds are essential to organofluorine chemistry. In exploring fluorine-containing building blocks, the following considerations are important: ease of preparation and commercial availability of the starting material and wide applicability of the fluorine-containing intermediate derived therefrom. As we know, trifluoropropene (TFP) is one of the readily available and economically feasible fluoro material. Recently, Ojima has studied in detail the carbonylation reactions of TFP catalyzed by transition metake TFP has also been used as a dienophile in Diels-Alder r e a ~ t i o n and , ~ it underwent Friedel-Crafts (1)Chinese Patent Appl. Serial No. CN 90 1 06105.0,Dec. 1990. (2)(a) Filler, R.; Kobayashi, Y. In Biomedicinal Aspects of Fluorine Chemistry; Kcdansha: Tokyo, 1983. (b) Welch, J. T. Tetrahedron 1987, 43,3123. (3) (a) Fuchigami, T. J. Synth. Org. Chem. Jpn. 1984,42,775. (b) Hewitt, C.D.; Silvester, M. J. Aldrichimica Acta 1988,21(1),3. (4)(a) Wiemers, D. W.; Burton, D. J. J. Am. Chem. SOC.1986,108,832 and references cited therein. (b) Umemoto, T.; Ando, A. Bull. Chem. SOC. Jpn. 1986,59,447. (c) Kitazume, T.; Ishikawa, N. J. Am. Chem. SOC. 1985,107,5186 and references cited therein. (5)(a) Boswell, G.A., Jr.; Ripka, T. C.; Schribner, R. M.; Tillock, C. W. Og.React. 1974,21,1. (b) Umemoto, T.; Tomita, K. Tetrahedron Lett. 1986,27,3271. (c) Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986,27,4465. (6) Purrington, S. T.; Evertt, T. S.; Bungardner, C. L. Tetrahedron Lett. 1984,25,1329. (7)(a) Drakesmith, F. G.; Steward, 0. J.; Tarrant, P. J. Org. Chem. 1967,33,280.(b) Yokozawa, T.; Nakai, T.; Ishikawa, N. Tetrahedron Lett. 1984,25,3987and 3991. (c) Yamazaki, T.; Ishikawa, N. Chem. Lett. 1984,521. (d) Yokozawa, T.; Ishikawa, N.; Nakai, T. Chem. Lett. 1987, 1971. (e) Fuchigami, T.; Nakagawa, Y. J. Org. Chem. 1987,52,5276.(f) Morikawa, T.; Nishiwaki, T.; Kobayashi, Y. Tetrahedron Lett. 1989,30, 2407. (9) Ojima, I.; Kato, K.; Nakahashi, K. J.Org. Chem. 1989,54,4511. (h) Prakash, G.K. S.; Krishnamarti, R.; Olah, G. A. J.Am. Chem. SOC. 1989,111,393.(i) Yamazaki, T.; Ishikawa, N.; Iwatsubo, H.; Kitazume, T. J.Chem. Soc., Chem. Commun. 1987,1340. 6)Hanzawa, Y.; Kawagoe, K.; Yamada, A.; Kobayashi, Y. Tetrahedron Lett. 1985,26, 219. (k) Uneyama, K.; Momota, M. Bull. Chem. SOC.Jpn. 1989,62,3378.(1) Shi, G.;Xu, Y. J. Chem. SOC.,Chem. Commun. 1989,607. (8)Ojima, I. Chem. Reo. 1988,88,1011. (9)(a) Mcbee, E.T.; Hsu, C. G.; Pierce, 0. R.; Roberts, C. W. J . Am. Chem. SOC. 1955,77,915.(b) Gacde, B.; Balthazor, T. B. J. Org. Chem. 1983,48,276.(c) Ojima, I., Yatabe, M., Fuchigami, T. J . Org.Chem. 1982, 47,2051.
0022-3263/91/1956-7336$02.50/0
7
a
1.0 1.0 1.0
THF DME DMF
6019
100 100 100
6719 4013
93 90 30
"Mole ratio of BTFP and Zn (Ag) w a ~1:1.5; Zn(Ag) was activated by TMSC1.14 b T h e conversion and yield were determined by 19FNMR versus C6H5CF3.
reaction with aromatic compounds to afford antiinflammatory agenta.1° 2-Bromotrifluoropropene (BTFP) (l), a derivative of TFP, could be easily obtained by dehydrobromination of the dibromo compound of TFP in high yield;" however, its utilization as a possible precursor of a-(trifluoromethy1)ethenyl carbanion synthetic equivalent only has been rarely expl~ited.'~J~ In the course of our research on the synthesis of fluorine-containing building blocks, we became interested in exploring the preparation of trifluoroisopropenylmetal reagents since it occurred to us that these reagents would be useful and versatile ones for introducing the trifluoroisopropenyl moiety into organic molecules. Drakesmith et al.7a have reported that trifluoroisopropenyllithium formed by the exchange metalation of BTFP with butyllithium was quite unstable; it underwent extremely facile defluorination above -90 "C and thus severely limited ita use. It is known that the defluorination of a-CF3-attached carbanion is assisted by countercations (e.g., K+, Na+, Li+) with a strong affinity for the fluorine at0m;l3 therefore, it could be anticipated that the use of counteractions with a weak affinity for the fluorine atom would impede the defluorination process. On the basis of this premise, we sought to prepare a trifluoroisopropenylmethyl reagent which would be stable and easy to handle. Herein, we would like to describe the successful preparation of trifluoroisopropenylzinc reagent (TFPZ) from 2-bromotrifluoropropene and the coupling reaction of this zinc reagent with aryl halides promoted by palladium. Initially, we attempted to prepare the zinc reagent by the direct reaction of BTFP with activated zinc powder in a solvent such as diethyl ether, THF, and DME. However, it failed to form the desired product in any noticeable amount and the starting BTFP was recovered. After many trials, we found that the addition of tetramethylethylenediamine (TMEDA) to a mixture of BTFP and Zn(Ag) couple in THF can bring about a clean formation of the zinc reagent 2 (eq 11,which displayed a single signal in 19FNMR at dTFA -16.0 ppm. + Zn(Ag)
r$:
-
9TMEDA
TMEDA
ZnBr
1
>-)
(z c 4
(1)
2
(10)Kumadaki, I. J. Synth. Org. Chem. Jpn. 1984,42,786. (11)Henne, A. L.;Nager, M. J. Am. Chem. SOC.1951,73, 1042. (12)Fuchigami, T.; Yamanouchi, A.; Ojima, I. Synthesis 1984,766. (13)Fuchigami, T.; Nakagawa, Y. J. O g . Chem. 1987,52,5276. (14)On addition of trimethylchlorosilane, the Zn(Ag) couple became spongy and much more reactive. Without trimethylchlorosilane, the reaction proceeded sluggishly and the reagent 2 was found to be formed only in low yield. Knochel15 has also noted the activation of zinc by trimethylchlorosilane in the presence of 1,2-dibromoethane. (15)Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988,53,2392.
0 1991 American Chemical Society
J. Org. Chem., Vol. 56, No. 26, 1991 7337
Notes The optimum condition for the synthesis of trifluoroisopropenylzincreagent has been examined, and the results were summarized in Table I. It reveals that the addition of TMEDA was essential to the formation of trifluoroisopropenylzincreagent. In THF, an excellent yield (93%) of TFPZ can be achieved by the reaction of BTFP with Zn(Ag) (mole ratio, 1:1.5) in the presence of 1mol equiv of TMEDA (Table I, entry 6). DME and diethyl ether can also be used as solvent for the preparation of TFPZ (Table I, entries 7 and 3). In DMF, however, only rather poor yield of TFPZ was obtained possibly due to the occurrence of a-defluorination (Table I, entry 8). It seems reasonable to assume a chelate structure (tetracoordinated zinc) such as 3 for TFPZ. The formation
-
u
3
of a tetrahedral complex with sp3 hybridization of the zinc atom is expected in view of its 3dI04s2electron configuration.I6 By the presence of a strong electron-withdrawing CF3group in the a-position, negative charge is being pulled away from the zinc atom causing the electron affinity of the vacant orbitals of zinc and, consequently, the tendency to form donor-acceptor complex to be increased. As a result, the covalent character of the zinc-carbon bond would be enhanced and the tendency of undergoing adefluorination would be suppressed. Indeed, we found that this TMEDA-complexed trifluoroisopropenylzincreagent in THF is quite thermally stable and it can be stored at room temperature over months or heated at 70 OC for a prolonged time in the absence of air and moisture showing no sign of deterioration. In modern organic synthesis, the cross-coupling of organometallic reagents with various electrophiles in the presence of a catalytic amount of palladium has been shown to be an efficient method for the formation of a carbon-carbon bond.I7 Recently, Burton18 and SauvetreIg have reported the cross-coupling of perfluorovinylzinc reagents with aryl iodides. Encouraged by the easy preparation and remarkable stability of the TFPZ (2),we were interested in the feasibility of using this reagent for undergoing cross-coupling reaction with electrophiles in the presence of transition metals. Gratifyingly, we found that TFPZ (2) was able to undergo the coupling reaction with various aryl halides (X = I, Br) promoted by palladium with normal reactivity to afford the important a(trifluoromethy1)styrenederivatives in good yields (eq 2). 2 +
ArX ( X = I, Br)
Cat.
Pd (PPho), THF
J:r 4a-I
The experimental results were summarized in Table 11. With aryl iodides, the coupling reaction of 2 (2 mol equiv) proceeded smoothly in the presence of 2 mol % Pd(PPh3), at 45-50 "C in THF. Reactions were completed in less than 6 h, and the corresponding coupling products were obtained in high yields (Table 11, entries 1-4). In the case of 4-bromoiodobenzene, the bromine substituent in the benzene ring remained intact under the given conditions (16)Noltes, J. G.; Van Den Hurk, J. W. G. J. Organomet. Chem. 1964,
and 4-bromotrifluoromethylstyrene (4d) was obtained as the sole product in 92% yield (Table 11, entry 4). Nevertheless, the coupling reaction with 2 could be extended to aryl bromides by carrying out the reaction at THF refluxing temperature for a prolonged time (16-20 h) and the corresponding coupling products were formed in satisfactory yields20 (Table 11, entries 5-11). Aryl bromides bearing a nitro or formyl group in the ortho position were found to be somewhat sluggish toward the coupling reaction with 2, possibly due to steric reasons, and an incremental addition of another 2 mol % of palladium catalyst was required at the end of 10 h during the course of reaction (Table 11, entries 8-10). In addition, 1-naphthyl iodide, 2-naphthyl bromide, and 6-methoxy-2-naphthyl bromide also underwent the palladium-catalyzed coupling reaction with 2 to give the corresponding coupling products 4j-1 in nearly quantitative yields (Table 11, entries 12-14). However, o-amino- and acetylamino-substituted bromobenzene failed to react with 2 under our reaction conditions. A lot of a-methylarylacetic acids, including Naproxen, are known to possess good antiinflammatory and analgesic properties. Among these, a fluorine containing analogue, acid) Flurbiprofen ((3-fluorobiphenyly1)-1-a-methylacetic is a very effective antiinflammatory agent with few side effects.21 The ready availability of a-(trifluoromethy1)styrene derivatives by the abovementioned coupling reaction of 2 with aryl halides led us to exploit the synthesis of trifluoro analogues of a-methylarylacetic acid therefrom. Thus, 6-methoxy-2-(a-(trifluoromethyl)ethenyl)naphthalene (41) was allowed to react with borane followed by treatment with alkaline hydrogen peroxide; the resultant alcohol without isolation was directly subjected to Jones' oxidation to afford the trifluoro analogue of Naproxen (5) in 69% yield (eq 3). c F3 C Fq 1. BH3-Me2S 2. t+O$,F(aOH
c 3. Jones' oxidn.
Me0 41
Me0 5
In conclusion, we have succeeded in preparing the trifluoroisopropenylzinc reagent from readily available 2bromotrifluoropropene. This zinc reagent acts as an a(trifluoromethy1)ethenyl carbanion synthetic equivalent without the occurrence of defluorination and can undergo palladium-catalyzed coupling reactions with aryl halides to afford a series of useful a-(trifluoromethy1)styrenederivatives in good yields. As a demonstration of the utility of these trifluoro-containing intermediates, compound 41 has been transformed to the trifluoro analogue of Naproxen (5). The biological property of 5 is under investigation.
Experimental Section 'HNMR spectra were recorded on a Varian EM-360A spectra with TMS as an internal standard. 19FNMR spectra were obtained on a Varian EM-360L spectrometer with trifluoroacetic acid (6 0.00) as an external standard; downfield shifts were designated negative. IR spectra were taken on a Shimadzu 440-m spectrometer, and mass spectra were done on a Finnigan 4021 GC/MS/DC intrument. All reactions as well as column chromatography were monitored routinely with the aid of TLC or '9F NMR spectroscopy. THF was distilled from LiAlH& Zn(Ag) was prepared according to the method described by Conia.22 Pd(PPhJ4 was obtained
1, 377.
(17)Negishi, E. I. Current Trends in Organic Synthesis, IUPAC; Nozaki, H., Ed.; Pergamon Press: New York, 1983;p 269. (18)Heize, P. L.;Burton, D. J. J. Org. Chem. 1988,53, 2714. (19)Gillet, J. P.; Sauvetre, R.; Normant, J. F. Synthesis 1986, 538.
(20)Burton'" reported that perfluorovinylzinc reagent failed to react with aryl bromides in the presence of palladium catalyst. (21)Shen, T. Y. Angew. Chem., Int. E d . Engl. 1972,11, 460.
Notes
7338 J. Org. Chem., Vol. 56,No. 26, 1991 Table 11. Palladium-CatalyzedCross-Couplingof TFPZ (2) with Aryl Halides entry
ArX
1
reaction condun*temp ("C)/time (h)
y ie1d 8e
productad
4516
(9%)
96
4a
4516
95 O& 4b
3
5015
92
5015.5
92
67/16
93
67/16
88
67/18
90
8
67/2oC
80
9
67/1gC
81
10
67/20'
86
11
67/20
a3
12
6716
99
13
6718
7 CH3C
11
0
4j
98
4k
J. Org. Chem., Vol. 56, No. 26, 1991
Notes
entry 14
ArX
Table I1 (Continued) reaction condosbtemp ("C)/time (h)
7339
yields' productad
(%)
86
67/16
41
'Mole ratio of aryl halide to 2 was 1:2. b 2 mol % of Pd(PPh3)4based on aryl halide was used as catalyst unless otherwise stated. 'Another 2 mol % of Pd(PPh3), was added at the end of 10 h. dAll products were fully characterized by 'H NMR, O ' F NMR, IR, MS, and C, H, F elemental analyses. e Isolated product yield based on aryl halide. by the method of Coulson.23 All reactions were carried out under nitrogen atmosphere. Trifluoroisopropenylzinc Reagent (2). To a suspension of Zn(Ag) (2.5 g, 38 mmol) in THF (20 mL) was added trimethylchlorosilane (0.5 mL) during stirring. After 10 min, tetramethylethylenediamine (6 mL, 25 mmol) was added and then 2-bromotrifluoropropene (4.4 g, 25 mmol) was added dropwise at room temperature. After addition, the mixture was heated at 60 OC for 9 h. After being cooled to room temperature, the resulting solution of 2 in THF was transferred to a bottle with a septum under nitrogen and stored as such. The yield of 2 was shown to be 93% as determined by 19FNMR versus PhCF3. 2 displayed a single peak at 6 -16.0 in 19FNMR. General Procedure for the Coupling of 2 with Aryl Halides. To the abovementioned zinc reagent 2 in THF (20 mL, ca. 20 mmol) was added Pd(PPh3)4(0.2 mmol) and aryl halide (10 mmol). The mixture was then allowed to heat at 45-67 OC for 5-20 h (seeTable 11). After being cooled, the reaction mixture was poured into n-hexane (100 mL), and the solid which precipitated was triturated and fdtered. The fdtrate was concentrated in vacuo, and the residue thus obtained was purified by shorbpath distillation under reduced pressure (for compounds 4a, 4c) or by flash column chromatography on silica gel using a 100.1mixture of petroleum ether (60-90 "C) and ethyl acetate as the eluent. In the case where the aryl halide used was 2-nitrobromobenzene, 2,4dinitrobromobenzene, or 2-bromobenzaldehyde, another 2 mol % of Pd(PPh3)4was added at the end of 10 h during the course of the reaction. a-(Trifluoromethy1)styrene (4a): colorless oil; 'H NMR (CDC13) 6 5.72 (8, 1 H), 5.92 (8, 1 H), 7.42 (8, 5 H); lgF NMR (CDC13) 6 -11.0 ( 8 ) ; IR (neat) 1580, 1500, 1380 cm-'; MS m / z (relative intensity) 172 (M, 37), 103 (62), 78 (100). Anal. Calcd for C4H7F3: C, 62.79; H, 4.10; F, 33.11. Found C, 62.27; H, 4.25; F, 33.18. 4-Nitro-a-(trifluoromethyl)styrene(4b): pale yellow oil; 'H N M R (CDC13) 6 5.90 (8, 1H), 6.20 (8, 1H), 7.12-7.60, centered at 7.39 (A2B2,J = 4 Hz, 4 H); 19FNMR (CDC13)6 -12.0 ( 8 ) ; IR (neat) 1600,1540,1500, 1380 cm-'; MS m/z (relative intensity) 217 (M, 100), 171 (28), 151 (32);Anal. Calcd for C9H6F3NO2:C, 49.78; H, 2.79; N, 6.45; F, 26.25. Found C, 49.98; H, 2.71; N, 6.41; F, 26.57. 3-Nitro-a-(trifluoromethyl)styrene(4c): pale yellow oil; 'H NMR (CDCl,) 6 5.92 (s, 1 H), 6.15 (8, 1 H), 7.10-7.80 (m, 3 H), 8.34 (s, 1H); 19FNMR (CDC13) 6 -11.0 ( 8 ) ; IR (neat) 1620, 1580,1540,1500,1358 cm-'; MS m/z (relative intensity) 217 (M, loo), 171 (33), 151 (35). Anal. Calcd for C9H6F3N02:C, 49.78; H, 2.79; N, 6.45; F, 26.25. Found: C, 49.80; H, 2.51; N, 6.14; F, 26.30. 4-Bromo-a-(trifluoromethyl)styrene (4d): colorless oil; 'H NMR (CDC13)6 5.73 (9, 1H), 5.95 (9, 1 H), 7.10-7.58, centered at 7.36 (A2B2,J = 4 Hz, 4 H); 19FNMR (CDC13)6 -12.0 (8); IR (neat) 1600,1500,1359cm-'; MS m / z (relative intensity) 252 (M + 1, loo), 231 (141,182 (49), 102 (38). And. Calcd for C91-&BrF3: C, 43.06; H, 2.41; F, 22.70; Found: C, 43.41; H, 2.31; F, 22.79. 4-Acetyl-a-(trifluoromethyl)styrene(4e): colorless oil; 'H NMR (CDCl,) 6 2.50 (s,3 H), 5.72 (9, 1H), 6.00 (8, 1H), 7.12-7.60, centered at 7.37 (A2B2,J = 4 Hz, 4 H);l9FNMR (CDC13)6 -11.5 (9); IR (neat) 1690, 1600, 1500, 1358 cm-'; MS m / z (relative intensity) 214 (M, 100). Anal. Calcd for CllH9F3O: C, 61.60; H, (22) Rousseau, G.;Conia, J. M. Tetrahedron Lett. 1981,22, 649. (23) Coulson, D.R.Inorg. Synth. 1972,13, 121.
4.23; F, 26.61; Found: C, 61.67; H, 4.60; F, 26.83. 2-Nitro-a-(trifluoromethyl)styrene(4f): pale yellow oil; 'H NMR (CDC13)6 5.76 ( 8 , 1 H), 6.21 (8, 1 H), 7.20-7.40 (m, 4 H); 19FNMR (CDC13)6 -11.8 (9); IR (neat), 1610, 1540, 1500, 1360 loo), 171 (30), 151 (41), cm-'; MS m/z (relative intensity) 217 (M, 102 (25). Anal. Calcd for CgI-&F3N02:C, 49.78; H, 2.79; N, 6.45; F, 26.25. Found C, 49.89; H, 2.51; N, 6.90; F, 26.30. 2,4-Dinitro-a-(trifluoromethyl)atyrene (4g): yellow oil; 'H NMR (CDC13)6 5.78 ( 8 , 1H), 6.20 (8, 1 €7.70 I), (d, J = 4 Hz, 1 H), 8.58 (dd, J 4 and 1.5 Hz, 1H); "F NMR (CDC13) 6 -11.0 (e); IR (neat) 1610,1550,1540,1510,1358cm-'; MS m/z (relative intensity) 263 (M + 1, 15), 243 (34)) 215 (42), 186 (100). Anal. Calcd for c$I$&o4: C, 41.24; H, 1.92; N, 10.69; F, 21.74; Found C, 41.55; H, 1.77; N, 10.42; F, 21.79. 2-Formyl-a-(trifluoromethyl)styrene (4h): colorless oil; 'H NMR (CDC13)6 5.54 (8, 1H), 6.15 (8, 1 H), 7.20-7.80 (m, 4 H), 10.00 (8, 1H); '4F N M R (CDC13) 6 -10.0 (9); IR (neat) 1710, 1610, 1600,1500cm-'; MS m/z (relative intensity) 201 (M + 1,98), 181 (37), 151 (77), 132 (100). Anal. Calcd for C10H7F30: C, 60.01; H, 3.53; F, 28.47; Found C, 60.30; H, 3.39; F, 28.42. 2-Acetoxy-a-(trifluoromethyl)styrene(4i): colorless oil; 'H NMR (CDC13) 6 2.00 ( ~ , H), 3 5.60 ( ~ ,H), l 6.18 (8,l H), 7.20-7.80 (m, 4 H); l4F NMR (CDC1,) 6 -120 (5); IR (neat) 1720,1610,1500, 1358 cm-l; MS m/z (relative intensity) 230 (M, loo), 211 (37), 187 (40). Anal. Calcd for CllH4F302: C, 57.40; H, 3.94; F, 24.76. Found C, 57.31; H, 4.26; F, 24.57. 1-(a-(Trifluoromethy1)ethenyl)naphthalene(4j): colorless oil; 'H NMR (CDC13) 6 5.83 (8, 1 H), 6.02 (8, 1H), 7.45 (m,7 H); 19FNMR (CDC13) 6 -12.4 ( 8 ) ; IR (neat) 1610, 1580, 1510, 1358 cm-';MS m/z (relative intensity) 222 (M, loo), 153 (60),128 (13). Anal. Calcd for C13Ha3: C, 70.27; H, 4.08; F, 25.05. Found C, 70.36; H, 4.16; F, 25.46. 2-(a-(Trifluoromethyl)ethenyl)naphthalene(4k): colorless oil;'H NMR (CDC13)6 5.86 (8, 1 H), 6.06 (9, 1H), 7.50 (m, 7 H); 19F NMR (CDC13)6 -12.6 (a); IR (neat) 1610,1580,1500, 1358 cm-'; MS m/z (relativeintensity) 222 (M, 100), 153 (57), 128 (20). Anal. Calcd for C13Ha3: C, 70.27; H, 4.08; F, 25.05. Found C, 70.11; H, 4.24; F, 25.33. 6-Met hoxy-2- (a-(trifluoromet hy1)et heny1)naphthalene (41): white solid; mp 68-69 OC; 'H NMR (CDC13) 6 3.90 (s,3 H), 5.82 (8, 1H), 6.01 ( 8 , 1H), 7.50 (m, 6 HI; '9 NMR (CDCl,) 6 -13.0 ( 8 ) ; IR (KC1) 1600, 1580, 1500, 1358 cm-'; MS m / z (relative intensity) 252 (M, 100),209 (71), 183 (17), 139 (35). Anal. Calcd for C14HllF30: C, 66.66; H, 4.40; F, 22.60. Found C, 66.42; H, 4.23; F, 22.42. 6-Methoxy-a-(trifluoromethyl)-2-naphthaleneaceticacid (5). To a solution of 41 (504 mg, 2 mmol) in DME (5 mL) was added BH3.Me2S (10 M, 0.3 mL, 3 mmol), and the reaction mixture was refluxed for 8 h. After the mixture was cooled to 0 OC, 50% aqueous NaOH solution (0.5 mL), ethanol (1 mL),and 30% H202(0.4 mL) were added successively. The mixture was then stirred for 30 min and diluted with ethyl acetate (15 mL). The organic layer was washed with saturated NaHC03 solution (2 X 5 mL) and brine (2 X 5 mL) and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue thus obtained was dissolved in acetone (5 mL) at 0 OC and treated with Jones' reagent24 (0.5 mL) for 1 h. After being quenched with 2-propanol (0.5 mL), the mixture was extracted with ethyl ether (3 X 5 mL) and the ethereal extract then was washed with 1 N (24) Cainell, G.; Cardillo, G. In Chromium Oxidation in Organic Chemistry; Springer-Verlag: New York, 1984; p 132.
J. Org. Chem. 1991,56, 7340-7341
7340
NaOH (3 X 5 mL). The alkaline solution was acidified with 2 N H2S04,and the solid which precipitated was extracted with ethyl ether (3 X 5 mL). The ethereal solution was washed with brine (3 X 5 mL) and dried over anhydrous Na2S04. The solvent was removed in vacuo, and the crude product was purified by flash column chromatographyon silica gel using petroleum ether (60-90 "C)/ethyl acetate (7:3) as the eluent to afford 5 (390 mg, 69% yield): a white solid, mp 140-142 "C; 'H NMR (CDCl,) 6 3.93 (8, 3 H), 4.49 (4,JH-F = 8.5 Hz, 1 H), 7.50 (m, 6 H); 19FNMR (CDClJ 6 -7.0 (d, JH-F = 8.5 Hz); IR (KCl) 3500, 1710, 1600, 1500, 1358 cm-'; MS m/z (relative intensity) 284 (M, 62), 239 (100). Anal. Calcd for CI4HllF3O3:C, 59.16; H, 3.90; F, 20.05. Found: C, 59.27; H, 4.29; F,20.17.
Acknowledgment. We gratefully acknowledge financial support from National Science Foundation of China and from Academic Sinica. Registry No. 1, 1514-82-5; 2, 136476-22-7; 4a, 384-64-5; 4b, 136476-181; 4c, 136476-19-2; 4a, 136476-20-5; 4e,136476-23-8; 4f, 136476-24-9; 4g, 136476-25-0;4h, 136476-26-1;4i, 136476-27-2; 4j, 136476-28-3;4k, 136476-29-4; 41,136476-30-7; 5,87406-13-1; iodobenzene, 591-50-4; p-iodonitrobenzene, 636-98-6; m-iodonitrobenzene, 645-00-1; p-bromoiodobenzene, 589-87-7; pbromonitrobenzene, 586-78-7;m-bromonitrobenzene, 585-79-5; p-bromoacetophenone, 99-90-1; o-bromonitrobenzene, 577-19-5; 2,4-dinitrobromobenzene, 584-48-5; o-bromobenzaldehyde, 6630-33-7; o-bromophenyl acetate, 1829-37-4; 1-iodonaphthalene, 90-14-2; 2-bromonaphthalene, 580-13-2; 2-bromo-6-methoxynaphthalene, 5111-65-9; silverzinc couple, 12041-17-7.
Mechanistic Studies on DNA Photolyase. 4. The Enthalpy of Cleavage of a Model Photodimer Hermhio P. Diogo,' Albert0 R. Dias,' Adil Dhalla,' Manuel E. Minas da Piedade,' and Tadhg P. Begley*J Centro de Quimica Estrutural, Complex0 1, Imtituto Superior Tgcnico, 10% Lisboa Codex, Portugal, and Department of Chemistry, Cornell University, Ithaca, New York 14853 Received February 1, 1991 (Revised Manuscript Received August 6, 1991)
Cyclobutane pyrimidine photodimers constitute the highest quantum yield lethal damage caused to DNA by ultraviolet light.' In the cell this lesion can be efficiently repaired by DNA photolyase in a light-dependent reaction (350-450 nm, eq 1).* While model studies using quinones
and indoles as sensitizers have demonstrated that both the photodimer radical cation and anion undergo facile fragmentation reaction^,^ the mechanism of this interesting reaction has not yet been clearly e~tablished.~.~ In this paper, we report the enthalpy of cleavage of a model uracil photodimer.6
Experimental Section Melting points were uncorrected. Microanalyses were performed by Guelph Chemical Laboratories. Chromatography was carried out on silica gel. 3-(3-Bromopropyl)-1-(carbomet hoxymethyl)uracil (4). Three grams (0.016 mol) of 3' was combined with 6.5 mL (13 g, 'Portugal. New York.
*
0022-3263/91/1956-7340$02.50/0
COOMe a
COOMe
(a) 1,3-Dibromopropane; (b) 1-methyluracil;(c) hu.
0.064 mol) of 1,3-dibromopropaneand 6.63 g (0.048 mol) of dry finely ground K2C03in 30 mL of dry DMF and heated at 60 OC for 1.5 h. The reaction mixture was cooled to room temperature and fitered, and the solvent was removed. Chromatography (0.5% CH30H in CH2C12)gave 3.7 g (75%) of 4: 'H NMR 6 7.65 (d, J = 9 Hz, 1 H), 5.75 (d, J = 9 Hz, 1 H), 4.6 (8, 2 H), 3.9 (t, J = 6 Hz, 2 H), 3.65 (8, 3 H), 3.5 (t,J = 6 Hz, 2 H), 1.9-2.1 (m, 2 H); HRMS calcd for CloH1,N20,Br 305.0143, found 305.0137. Bisuracil (5). 4 (2.6 g, 8.5 mmol), 1.0 g (8.5 mmol) of 1methyluracil? and 3.5 g (25.5 mmol) of K&03 in 40 mL of dry DMF were heated at 60 OC for 1.5 h. The reaction mixture was filtered, and the solvent was removed. Chromatography (1% CH30H in CH2C12)gave 2.3 g (78%) of 5: mp 176-178 "C; 'H NMR 6 7.6 ( d , J = 9 Hz, 2 H), 5.75 ( d , J = 9 Hz, 1 H),5.65 (d, J = 9 Hz, 1 H), 4.6 (s,2 H), 3.75 (t, J = 6 Hz, 4 H), 3.65 (s,3 H), 3.3 (8,3 H), 1.6-1.8 (m, 2 H). Anal. Calcd for CI5Hl8O6N4:C, 51.43; H, 5.18; N, 15.99. Found: C, 51.28; H, 4.91; N, 15.75. Cis-Syn Photodimer 6. One gram of 5 was dissolved in 500 mL of CH3CN and degassed by purging with argon for 15 min; 50 mL of acetone was added, and the solution was irradiated in a Rayonet reactor (Amm = 300 nm) for 10 h. The solvent was removed, and the photodimer was purified by chromatography (1% CHBOHin CH2C12)to give 0.63 g (63%) of 6: mp 253-255 "C; 'H NMR 6 3.65-4.45 (multiplet, 10 H), 3.63 (e, 3 H), 2.8 (8, 3 H), 2.0-2.2 (m, 1 H), 1.4-1.6 (m, 1 H). Anal. Calcd for C16H1806N~C, 51.43; H, 5.18; N, 15.99. Found: C, 51.81; H, 5.35; N, 16.09. Combustion Calorimetry. The standard enthalpies of formation of bisuracil5 and ita photodimer 6 were measured using a mini rotating-bombcombustion calorimeter suitable for samples of ca. 10-50 mg.9 The compounds were burned as pellets (ca. 20 mg) under 30 atm of oxygen using n-hexadecane (ca. 4 mg) as combustion aid. The bomb was not rotated during the experiments. The HNOBformed was determined as NO3- using a Dionex 4000i ion chromatography apparatus.
Results and Discussion The model photodimer was synthesized as outlined in Scheme I. The trimethylene linker ensured that only the syn-cis isomer resulted from the photodimerization reaction.1° The standard enthalpy of formation of bisuracil5 and its photodimer 6 were found to be -1116.6 f 3.7 kJ/mol (1) For a recent review: Cadet, J.; Vigny, P. Bioorganic Photochemistry; Morrison, H., Ed.; Wiley: New York, 1990; Vol. 1, p 1. (2) For a recent review: Mvles. - . G . M.: Sancar. A. Chem. Res. Toxicol. 1989, 2,197. (3) (a) Lamola, A. A. Mol. Photochem. 1972,4, 107. (b) Roth, H. D.; Lamola, A. A. J.Am. Chem. SOC.1972,94, 1013. (c) Helene, C.; Charlier, M. Photochem. Photobiol. 1977,25, 429. (d) Van Camp, J. R.; Young, T.; Hartmann, R. F.; Rme, S.D. Photochem. Photobiol. 1987,45,365. (e) Kim, S.-T.; Rose, S. D. J. Phys. Org. Chem. 1990,3, 581. (4) Witmer, M. R.; Altmann, E.; Young, H.; Begley, T. P.; Sancar, A. J. Am. Chem. SOC.1989,111, 9264. (5) Okamura, T.; Sancar, A,; Heelis, P. F.; Begley, T. P.; Hirata, Y.; Mataga, N. J.Am. Chem. SOC.1991,113, 3143. (6)The corresponding deoxyuridine dinucleotide photodimer is a substrate for the E. coli DNA photolyase (ref 4). (7) Jones, A. S.;Lewis, P.; Withers, S.F. Tetrahedron 1973,29,2293. ( 8 ) Browne, D. T.;Eisinger, J.; Leonard, N. J. J.Am. Chem. SOC.1968, 90,7302. (9) (a) Minson, M.; Randzio, S.;Sunner, S.5th International Conference on Chemical Thermodynamics, Ronneby, Sweden, 1977, p 54. (b) Minson, M. Pure Appl. Chem. 1983,55,419. (c) Dias, A. R.; Diogo, H. P.; Minas da Piedade, M. E.; Pilcher, G.11th International Conference on Chemical Thermodynamics, Como, Italy, 1990, p 290. (IO) Leonard, N. L.; Cundall, R. L. J.Am. Chem. SOC.1974,96,5904.
0 1991 American Chemical Society
